NO334612B1 - Stabilization of macrolides - Google Patents

Stabilization of macrolides Download PDF

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NO334612B1
NO334612B1 NO20121113A NO20121113A NO334612B1 NO 334612 B1 NO334612 B1 NO 334612B1 NO 20121113 A NO20121113 A NO 20121113A NO 20121113 A NO20121113 A NO 20121113A NO 334612 B1 NO334612 B1 NO 334612B1
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rapamycin
hydroxy
mixture
macrolide
ethyl
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NO20121113L (en
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François Navarro
Samuel Petit
Guy Stone
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
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  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Oppfinnelsen vedrører stabilisering av 40-O-(2-hydroksy)etyl-rapamycin oppnådd på amorf form.The invention relates to the stabilization of 40-O- (2-hydroxy) ethyl rapamycin obtained in amorphous form.

Description

Den foreliggende oppfinnelsen vedrører en bulkblanding omfattende 40-O-(2-hydroksy)etyl-rapamycin på amorf form og 2,6-di-tert.-butyl-4-metylfenol, anvendelse av bulkblandingen til fremstilling av en farmasøytisk sammensetning, og en farmasøytisk sammensetning som omfatter nevnte bulkblandingen. The present invention relates to a bulk mixture comprising 40-O-(2-hydroxy)ethylrapamycin in amorphous form and 2,6-di-tert-butyl-4-methylphenol, use of the bulk mixture for the preparation of a pharmaceutical composition, and a pharmaceutical composition comprising said bulk mixture.

Håndteringen og lagringen spesielt i bulkform av farmasøytiske aktive ingredienser som er følsomme for oksidasjon er vanskelig. Spesialhåndtering er nødvendig og ofte lagres den oksidasjonsfølsomme ingrediensen i lufttette pakninger under beskyttende gass. Betydelige mengder av stabilisatorer tilsettes under formuleringsprosessen av slike farmasøytisk aktive ingredienser. The handling and storage, especially in bulk form, of pharmaceutical active ingredients which are sensitive to oxidation is difficult. Special handling is necessary and often the oxidation-sensitive ingredient is stored in airtight packages under protective gas. Significant amounts of stabilizers are added during the formulation process of such pharmaceutically active ingredients.

Polyen-makrolider har tilfredsstillende stabilitetsegenskaper. Imidlertid er det ikke funnet at deres stabilitet i forhold til oksygen kan vesentlig forbedres ved tilsetningen av en stabilisator, for eksempel en antioksidant, under deres isolasjonstrinn. Polyene macrolides have satisfactory stability properties. However, it has not been found that their stability to oxygen can be significantly improved by the addition of a stabilizer, such as an antioxidant, during their isolation step.

Ifølge oppfinnelsen er det tilveiebrakt According to the invention, it is provided

1. En bulkblanding omfattende 40-O-(2-hydroksy)etyl-rapamycin på amorf form og 2,6-di-tert.-butyl-4-metylfenol i en mengde på opptil 1% basert på vekten av 40-O-(2-hydroksy)etyl-rapamycin. 1. A bulk mixture comprising 40-O-(2-hydroxy)ethyl rapamycin in amorphous form and 2,6-di-tert-butyl-4-methylphenol in an amount of up to 1% based on the weight of 40-O- (2-Hydroxy)ethyl-rapamycin.

Fortrinnsvis er blandingen i en steril tilstand. Preferably, the mixture is in a sterile state.

Som alternativer til den foreliggende oppfinnlesen over tilveiebringes også: As alternatives to the present invention above, the following are also provided:

2. Anvendelse av blanding ifølge pkt. 1, til framstilling av en farmasøytisk sammensetning. 2. Use of the mixture according to point 1, for the preparation of a pharmaceutical composition.

Rapamycin er et kjent laktam-makrolid som kan fremstilles ved for eksempel Streptom<y>ces h<y>groscopicus. Strukturen av rapamycin er gitt i Kessler, H. Et al.; 1993; Heiv. Chim. Acta. 76: 117. Rapamycin har antibiotiske og irnmunsuppressive egenskaper. Derivater av rapamycin er kjente, for eksempel 16-O-substituerte rapamyciner, for eksempel som beskrevet i WO 94/02136 og WO 96/41807,40-O-substituerte rapamyciner, for eksempel som beskrevet i WO 94/09010, WO 92/05179, WO 95/14023, 94/02136, WO 94/02385 og WO 96/13273, hvorved alle disse her er innarbeidet ved referanse. Foretrukne rapamycinderivater er for eksempel rapamyciner der hydroksy i posisjon 40 med formel A, som illustrert på side 1 i WO 94/09010, er erstattet med -OR, der R er hydroksyalkyl, hydroksyalkoksyalkyl, acylaminoalkyl eller aminoalkyl, for eksempel 4+-0-(2-hydroksy)etyl-rapamycin, 40-O-(3-hydroksy)propyl-rapamycin og 40-O-[2-(2-hydroksy)etoksy]etyl-rapamycin. Rapamycin is a known lactam macrolide which can be produced by, for example, Streptom<y>ces h<y>groscopicus. The structure of rapamycin is given in Kessler, H. Et al.; 1993; Hooray. Chim. Acta. 76: 117. Rapamycin has antibiotic and immunosuppressive properties. Derivatives of rapamycin are known, for example 16-O-substituted rapamycins, for example as described in WO 94/02136 and WO 96/41807, 40-O-substituted rapamycins, for example as described in WO 94/09010, WO 92/ 05179, WO 95/14023, 94/02136, WO 94/02385 and WO 96/13273, all of which are hereby incorporated by reference. Preferred rapamycin derivatives are, for example, rapamycins in which hydroxy in position 40 of formula A, as illustrated on page 1 of WO 94/09010, is replaced by -OR, where R is hydroxyalkyl, hydroxyalkylalkyl, acylaminoalkyl or aminoalkyl, for example 4+-0- (2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin and 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin.

Makroliden ved foreliggende oppfinnelse er 40-O-(2-hydroksy)etyl-rapamycin. The macrolide of the present invention is 40-O-(2-hydroxy)ethylrapamycin.

Antioksidanten ved foreliggende oppfinnelse er 2,6-di-tert.-butyl-4-metylfenol (heretter The antioxidant in the present invention is 2,6-di-tert-butyl-4-methylphenol (hereafter

BHT). BHT).

Antioksidanten kan tilsettes til polyen-makrolidet ved begynnelsen av isolasjonstrinnene, foretrukket slutt-isolasjonstrinnet, mer foretrukket rett før det siste utfellingstrinnet. Makroliden er foretruket i en renset tilstand. Den kan oppløses i et inert løsningsmiddel og antioksidanten tilsettes til den oppnådde løsningen, etterfulgt av et utfellingstrinn av den stabiliserte makroliden. The antioxidant can be added to the polyene macrolide at the beginning of the isolation steps, preferably the final isolation step, more preferably just before the last precipitation step. The macrolide is preferred in a purified state. It can be dissolved in an inert solvent and the antioxidant added to the resulting solution, followed by a precipitation step of the stabilized macrolide.

Det oppnådde stabiliserte makrolidet fremviser overraskende en forbedret stabilitet i forhold til oksidasjon og dets håndtering og lagring, eksempel i bulkform før dets videre bearbeiding for eksempel til en galenisk sammensetning, blir mye enklere. Det er spesielt interessant for makrolider på amorf form. The obtained stabilized macrolide surprisingly exhibits an improved stability in relation to oxidation and its handling and storage, for example in bulk form before its further processing for example into a galenic composition, becomes much easier. It is particularly interesting for macrolides in amorphous form.

Makrolidet som er stabilisert ifølge oppfinnelsen kan anvendes som sådan for frem-stillingen av den ønskede galeniske formuleringen. Slike formuleringer kan fremstilles ifølge fremgangsmåter som er kjente innenfor fagområdet, omfattende tilsetningen av ett eller flere farmasøytisk akseptable fortynningsmidler eller bærere, inkludert tilsetningen av ytterligere stabilisatorer om nødvendig. The macrolide which is stabilized according to the invention can be used as such for the preparation of the desired galenic formulation. Such formulations may be prepared according to methods known in the art, comprising the addition of one or more pharmaceutically acceptable diluents or carriers, including the addition of additional stabilizers if necessary.

Følgelig tilveiebringes videre: Accordingly, further provided:

3. En farmasøytisk sammensetning som omfatter, som aktiv ingrediens, en blanding ifølge pkt. 1 over, sammen med en eller flere farmasøytisk akseptable bærere eller fortynningsmidler. 3. A pharmaceutical composition comprising, as active ingredient, a mixture according to point 1 above, together with one or more pharmaceutically acceptable carriers or diluents.

De farmasøytiske sammensetningened ifølge oppfinnelsen kan inneholde ytterligere eksipienter, for eksempel et smøremiddel, et oppløsende middel, et overflateaktivt middel, en bærer, et fortynningsmiddel, en smaksforbedrer, etc. Det kan være på flytende form, for eksempel løsninger, suspensjoner eller sammensetninger, slik som en mikroemulsjon, for eksempel som beskrevet i US-patent 5,536,729, eller på fast form, for eksempel kapsler, tabletter, dragees, pulvere (inkludert mikroniserte eller på annen måte reduserte små partikler), faste dispersjoner, granulater, etc, for eksempel som beskrevet i WO 97/03654, hvorved innholdet av disse her er innarbeidet som referanse, eller semi-faste former, slik som salter, geler, kremer og pastaer. De tilpasses fortrinnsvis til en form som er egnet for oral administrering. Fortrinnsvis er de på fast form. De farmasøytiske sammensentingene ifølge oppfinnelsen kan fremstilles ifølge kjente fremgangsmåter, ved å blande makroliden som er stabilisert ifølge oppfinnelsen med ytterligere ingredienser under røring; ingrediensene kan knuses eller males og, om nødvendig, komprimeres for eksempel til tabletter. The pharmaceutical compositions according to the invention may contain additional excipients, for example a lubricant, a dissolving agent, a surface-active agent, a carrier, a diluent, a flavor enhancer, etc. It may be in liquid form, for example solutions, suspensions or compositions, such as a microemulsion, for example as described in US Patent 5,536,729, or in solid form, for example capsules, tablets, dragees, powders (including micronized or otherwise reduced small particles), solid dispersions, granules, etc, for example as described in WO 97/03654, whereby the contents of these are incorporated here as a reference, or semi-solid forms, such as salts, gels, creams and pastes. They are preferably adapted to a form suitable for oral administration. Preferably they are in solid form. The pharmaceutical compositions according to the invention can be prepared according to known methods, by mixing the macrolide which is stabilized according to the invention with additional ingredients while stirring; the ingredients can be crushed or ground and, if necessary, compressed for example into tablets.

Sammenstningen ifølge oppfinnelsen er nyttige for indikasjonene som er kjente for makrolidet som den inneholder ved for eksempel kjente doseringer. For eksempel når makro Udet har immunsuppressive egenskaper, kan sammensetningen være nyttig for eksempel ved behandlingen eller forebyggingen av organ- eller vevakutt- eller kronisk allo- eller xeno-transplantasjonsawisning, autoimmune sykdommer eller inflammatoriske tilstander, astma, prolifererende forstyrrelser, for eksempel svulster, eller hyperprolifererende vaskulære sykdommer, foretrukket ved forebyggingen eller behandlingen av transplantasjonsawisning. The composition according to the invention is useful for the indications that are known for the macrolide that it contains at, for example, known dosages. For example, when macro Udet has immunosuppressive properties, the composition may be useful, for example, in the treatment or prevention of organ or tissue amputation or chronic allo- or xeno-transplant wasting, autoimmune diseases or inflammatory conditions, asthma, proliferative disorders, such as tumors, or hyperproliferative vascular diseases, preferably in the prevention or treatment of transplant rejection.

Mengden av makro lid og av sammensetningen som skal administreres avhenger av et antall faktorer, for eksempel den aktive ingrediensen som benyttes, tilstandene som skal behandles, varigheten av behandlingen etc. En egnet daglig doseringsform for oral administrering omfatter fra 0,1 til 10 mg, for administrasjon en gang eller på fordelt form. The amount of the macrolide and of the composition to be administered depends on a number of factors, for example the active ingredient used, the conditions to be treated, the duration of the treatment, etc. A suitable daily dosage form for oral administration comprises from 0.1 to 10 mg, for administration once or in distributed form.

Det følgende eksempel illustrerer oppfinnelsen uten å begrense den. The following example illustrates the invention without limiting it.

Eksempel: Fremstilling av stabilisert 40-O-(2-hydroksy)etyl-rapamycin Example: Preparation of stabilized 40-O-(2-hydroxy)ethyl rapamycin

100 g 40-O-(2-hydroksy)etyl-rapamycin oppløses i 600 liter absolutt etanol. Etter tilsetning av 0,2 g BHT tilsettes den oppnådde løsningen dråpevis med røring til 3,0 liter vann i løpet av 1 time. Den oppnådde suspensjonen røres i ytterligere 10 minutter. Filtrering med etterfølgende vaksing (3x200 ml vann/etanol ved et volum/volum-forhold på 5) resulterer i et fuktig hvitt produkt som ytterligere tørkes under vakuum (1 100 g of 40-O-(2-hydroxy)ethyl rapamycin is dissolved in 600 liters of absolute ethanol. After adding 0.2 g of BHT, the resulting solution is added dropwise with stirring to 3.0 liters of water over the course of 1 hour. The resulting suspension is stirred for a further 10 minutes. Filtration with subsequent vaccination (3x200 ml water/ethanol at a v/v ratio of 5) results in a moist white product which is further dried under vacuum (1

mbar) ved 30°C i 48n timer. Det oppnådde tørkede produktet inneholder 0,2 % mbar) at 30°C for 48n hours. The dried product obtained contains 0.2%

(vekt/vekt) BHT. (weight/weight) BHT.

Det oppnådde produktet viser forbedret stabilitet ved lagring. Summen av biprodukter og nedbrytningsprodukter i prosent etter 1 ukes lagring er som følger: The obtained product shows improved stability during storage. The sum of by-products and degradation products in percentage after 1 week of storage is as follows:

Claims (4)

1. En bulkblanding omfattende 40-O-(2-hydroksy)etyl-rapamycin på amorf form og 2,6-di-tert.-butyl-4-metylfenol i en mengde på opptil 1% basert på vekten av 40-O-(2-hydroksy)etyl-rapamycin.1. A bulk mixture comprising 40-O-(2-hydroxy)ethyl rapamycin in amorphous form and 2,6-di-tert-butyl-4-methylphenol in an amount of up to 1% based on the weight of 40-O-(2 -hydroxy)ethyl-rapamycin. 2. En bulkblanding ifølge krav 1, der blandingen er i en steril tilstand.2. A bulk mixture according to claim 1, wherein the mixture is in a sterile state. 3. Anvendelse av en blanding ifølge krav 1 eller 2, til framstilling av en farmasøytisk sammensetning.3. Use of a mixture according to claim 1 or 2, for the preparation of a pharmaceutical composition. 4. En farmasøytisk sammensetning som omfatter, som aktiv ingrediens, en blanding ifølge krav 1 eller 2 sammen med en eller flere farmasøytisk akseptable bærere eller fortynningsmidler.4. A pharmaceutical composition comprising, as active ingredient, a mixture according to claim 1 or 2 together with one or more pharmaceutically acceptable carriers or diluents.
NO20121113A 1998-12-07 2012-10-01 Stabilization of macrolides NO334612B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9826882.4A GB9826882D0 (en) 1998-12-07 1998-12-07 Organic compounds
GBGB9904934.8A GB9904934D0 (en) 1998-12-07 1999-03-04 Organic compounds
PCT/EP1999/009521 WO2000033878A2 (en) 1998-12-07 1999-12-06 Stabilization of macrolides

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NO20121113L NO20121113L (en) 2001-05-16
NO334612B1 true NO334612B1 (en) 2014-04-22

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NO20012424A NO332698B1 (en) 1998-12-07 2001-05-16 Method for stabilizing rapamycin derivatives
NO20121113A NO334612B1 (en) 1998-12-07 2012-10-01 Stabilization of macrolides

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